Lacosamide is reported for the first time in WO9733861 (corresponding U.S. Pat. No. 5,773,475) by Research Corporation Technologies, USA. It is also published in J. Med. Chem. 1996, 39, 1907-1916. According to this literature, lacosamide can be made in three routes. According to one route (Scheme-I), D-serine is converted to methyl ester and reacted with benzyl amine to get the
corresponding benzylamide. This intermediate is reacted with acetic anhydride to get the N-acetyl derivative. Methylation using methyl iodide in the presence of silver (I) oxide gave lacosamide. Overall yield of lacosamide by this route is 6.9%. This route is not commercially viable due to low yield and usage of costly reagent like silver oxide.
According to another route (Scheme-II) D-serine is reacted with acetic anhydride to get the corresponding N-acetyl derivative. This intermediate is reacted with benzylamine to get the corresponding benzylamide derivative which on methylation using methyl iodide and silver (I) oxide gave lacosamide. Overall yield of lacosamide by this route is 28.7%. This route is not commercially viable as it requires column chromatography in the amide intermediate (IV) isolation stage.

According to one more route described in the above reference, amino group of D-serine is protected by benzyl chloroformate and reacted with methyl iodide in the presence of silver oxide to get methyl ester of O-methyl derivative (Scheme-III). The ester is hydrolyzed and converted to benzylamide via mixed anhydride technique. The amino group protection is removed by hydrogenation and converted to lacosamide by acetylation using acetic anhydride. Overall yield of lacosamide by this route is 43.6%. This route is not commercially viable as it requires column chromatography in the amide intermediate (IV) isolation stage.

Slight variations of the process discussed in above Scheme-III are disclosed in Tetrahedron: Asymmetry 1998, 9, 3841-3854 (Scheme-IV).

According to one variation (A) in this report N-protected D-serine is reacted with methyl iodide to get O-methyl methyl ester compound of formula-VII. Compound of formula-VII is hydrogenated, N-acetylated, ester group hydrolyzed, and amidated with benzyl amine to get lacosamide of formula-I. Overall yield of lacosamide by this route is 37.3%. Lacosamide produced by this method contained about 15% of chiral impurity. Therefore, this route is not viable on commercial scale. In the second variation (B), N-protected D-serine is reacted with benzylamine to get the amide of formula-XIV. Compound of formula-XIV is hydrogenated, N-acetylated, and O-methylated to get lacosamide of formula-I. Overall yield of lacosamide by this route is 43.7%. This route is not commercially viable as it requires chromatography technique for purifications intermediate of formula-XIV. Lacosamide produced by this method contained no chiral impurity. In the third variation (C), compound of formula-XIV is O-methylated, hydrogenated and N-acetylated to get lacosamide of formula-I. Overall yield of lacosamide by this route is 50.8%. Lacosamide produced by this method contained no chiral impurity. This route is not viable on commercial scale as it requires chromatographic technique for purifications of some of the intermediates involved in the process.
An improved process for the preparation of lacosamide is disclosed in WO2006037574 (equivalent US application No. 2008027137). In this disclosed method D-serine is N-protected with Boc group and O-methylated with methylating agents such as methyl iodide and dimethyl sulphate (Scheme-V). The resultant compound of formula-XVII is reacted with benzylamine to get the corresponding amide of formula-XVIII. N-deprotection of Boc group from compound of formula-XVIII gave the compound of formula-X which on acetylation gave lacosamide of formula-I. Overall yield of lacosamide by this route is 43.7%. This route is not commercially viable as some of the intermediates involved in the process are liquids, which makes it difficult to purify them.

A novel process for the preparation of lacosamide is also disclosed in Bioorg. Med. Chem. 2008, 16, 8968-8975 starting from methyl ester of D-serine (Scheme-VI). Methyl ester of D-serine is converted to an aziridine intermediate of formula-XIX. N-acetylation of compound of formula-XIX followed by ring opening with methanol in the presence of an acid catalyst gave the compound of formula-XII. Ester hydrolysis of compound of formula-XII followed by reaction with benzylamine using DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride) gave lacosamide of formula-I. This route is not commercially viable as it requires usage of costly reagents like DTPP, DMTMM, lithium hydroxide, and BF3 etherate.

A process for the preparation of lacosamide is disclosed in US patent application No. 20090143472 using trityl group for N-protection of D-serine (Scheme-VII). In this process costly and polluting reagents like trimethylsilyl chloride, trityl chloride, hexamethyldisilazine, sodium hydride, methyl iodide were used. Therefore, this route is not commercially viable.

A process for the preparation of lacosamide is also disclosed in IPCOM #000181080D. In this disclosure phthalimido group is selected for N-protection of D-serine (Scheme-VIII).

Keeping in view of the difficulties in commercialization of the above-mentioned processes for the preparation of lacosamide, we aimed to develop a simple and economical process for commercial production of lacosamide.
We observed that a promising approach for a process for the preparation of lacosamide would be to (a) avoid the usage of costly and difficult to handle reagents; (b) avoid usage of chromatography technique; (c) and avoid the preparation of liquid intermediates at late stage of the synthesis.
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of lacosamide, which is commercially applicable.
Another objective of the present invention is to provide an improved process for the preparation of lacosamide avoiding the formation of liquid intermediates at late stage of the synthesis.